{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T07:38:59Z","timestamp":1773387539253,"version":"3.50.1"},"reference-count":37,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T00:00:00Z","timestamp":1613779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2020M3A9B302618221"],"award-info":[{"award-number":["2020M3A9B302618221"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003569","name":"Ministry of Food and Drug Safety","doi-asserted-by":"publisher","award":["18172MFDS182"],"award-info":[{"award-number":["18172MFDS182"]}],"id":[{"id":"10.13039\/501100003569","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hexapeptide WKYMVm (Trp-Lys-Tyr-Met-Val-D-Met), a ligand of formyl peptide receptor 2, exhibits anti-inflammatory and angiogenic properties in disease models. However, the therapeutic effects of WKYMVm on hepatic fibrosis have not been evaluated to date. Therefore, we investigated whether WKYMVm exerts antifibrotic effects and induces vascular regeneration in a rat model of bile duct ligation (BDL). The antifibrotic and angiogenic effects of WKYMVm on liver regeneration in the BDL rat model were analyzed using biochemical assays, qRT-PCR, western blotting, immunofluorescence, and immunohistochemistry. To determine the effects of WKYMVm on hepatic fibrosis and angiogenesis in vitro, we measured the expression levels of fibrotic factors in hepatic stellate cells (HSCs) and angiogenic factors in human umbilical vein endothelial cells (HUVECs). WKYMVm attenuated the expression of collagen type I (Col I) and \u03b1-smooth muscle actin (\u03b1-SMA) and significantly increased the levels of angiogenetic factors in the BDL model (p &lt; 0.05). WKYMVm reduced fibrotic marker expression in transforming growth factor (TGF)-\u03b2-induced HSCs and promoted angiogenic activity through tube formation in 5-Fluorouracil (FU)-treated HUVECs (p &lt; 0.05). Also, WKYMVm administration enhanced hepatocyte proliferation in BDL rats (p &lt; 0.05). The WKYMVm alleviates hepatic fibrosis by inhibiting HSC activation and promotes hepatic regeneration via vascular remodeling. These data suggest that the WKYMVm may be a new therapeutic agent for liver fibrosis.<\/jats:p>","DOI":"10.3390\/ijms22042107","type":"journal-article","created":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T13:17:02Z","timestamp":1613827022000},"page":"2107","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Formyl Peptide Receptor 2 Alleviates Hepatic Fibrosis in Liver Cirrhosis by Vascular Remodeling"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5716-8128","authenticated-orcid":false,"given":"Ji Hye","family":"Jun","sequence":"first","affiliation":[{"name":"Department of Biomedical Science, CHA University, Seongnam 13488, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soo Young","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, CHA University, Seongnam 13488, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9728-7065","authenticated-orcid":false,"given":"Sohae","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, CHA University, Seongnam 13488, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5476-7846","authenticated-orcid":false,"given":"Hee Jung","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, CHA University, Seongnam 13488, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae Yeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, CHA University, Seongnam 13488, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6649-8783","authenticated-orcid":false,"given":"Gyu Tae","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Si Hyun","family":"Bae","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Catholic University Medical College, Seoul 03312, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae Ho","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2320-7157","authenticated-orcid":false,"given":"Gi Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, CHA University, Seongnam 13488, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16041","DOI":"10.1038\/nrdp.2016.41","article-title":"Acute-on-chronic liver failure in cirrhosis","volume":"2","author":"Arroyo","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1016\/S0140-6736(14)60121-5","article-title":"Liver cirrhosis","volume":"383","author":"Tsochatzis","year":"2014","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1016\/j.jhep.2008.12.011","article-title":"Angiogenesis in liver disease","volume":"50","author":"Fernandez","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"48","DOI":"10.5604\/16652681.1226814","article-title":"Management strategies for liver fibrosis","volume":"16","year":"2017","journal-title":"Ann. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0168-8278(01)00260-4","article-title":"Hepatic stellate cell\/myofibroblast subpopulations in fibrotic human and rat livers","volume":"36","author":"Cassiman","year":"2002","journal-title":"J. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1002\/cphy.c120035","article-title":"Hepatic stellate cells and liver fibrosis","volume":"3","author":"Puche","year":"2013","journal-title":"Compr. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1136\/gutjnl-2014-306842","article-title":"Pathobiology of liver fibrosis: A translational success story","volume":"64","author":"Lee","year":"2015","journal-title":"Gut"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1007\/s12072-013-9483-7","article-title":"Angiogenesis in liver regeneration and fibrosis: \u201cA double-edged sword\u201d","volume":"7","author":"Kaur","year":"2013","journal-title":"Hepatol. Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.jhep.2016.07.009","article-title":"Liver sinusoidal endothelial cells: Physiology and role in liver diseases","volume":"66","author":"Poisson","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1053\/j.gastro.2014.01.061","article-title":"Vascular endothelial growth factor promotes fibrosis resolution and repair in mice","volume":"146","author":"Yang","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1177\/002215540104900112","article-title":"Expression and role of vascular endothelial growth factor in liver regeneration after partial hepatectomy in rats","volume":"49","author":"Taniguchi","year":"2001","journal-title":"J. Histochem. Cytochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/nature10144","article-title":"Molecular mechanisms and clinical applications of angiogenesis","volume":"473","author":"Carmeliet","year":"2011","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1172\/JCI66025","article-title":"Liver sinusoidal endothelial cells and liver regeneration","volume":"123","author":"DeLeve","year":"2013","journal-title":"J. Clin. Invest."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Cao, Z., Ye, T., Sun, Y., Ji, G., Shido, K., Chen, Y., Luo, L., Na, F., Li, X., and Huang, Z. (2017). Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis. Sci. Transl. Med., 9.","DOI":"10.1126\/scitranslmed.aai8710"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"16464","DOI":"10.1074\/jbc.M112274200","article-title":"Endostatin causes G1 arrest of endothelial cells through inhibition of cyclin D1","volume":"277","author":"Hanai","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8614","DOI":"10.1167\/iovs.14-15693","article-title":"The role of the hypoxia response in shaping retinal vascular development in the absence of Norrin\/Frizzled4 signaling","volume":"55","author":"Rattner","year":"2014","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1093\/cvr\/cvu133","article-title":"Frizzled7 controls vascular permeability through the Wnt-canonical pathway and cross-talk with endothelial cell junction complexes","volume":"103","author":"Peghaire","year":"2014","journal-title":"Cardiovasc. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/jcbfm.2013.213","article-title":"The Wnt\/planar cell polarity signaling pathway contributes to the integrity of tight junctions in brain endothelial cells","volume":"34","author":"Artus","year":"2014","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.tips.2010.04.001","article-title":"Are formyl peptide receptors novel targets for therapeutic intervention in ischaemia-reperfusion injury?","volume":"31","author":"Gavins","year":"2010","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1002\/stem.1578","article-title":"WKYMVm-induced activation of formyl peptide receptor 2 stimulates ischemic neovasculogenesis by promoting homing of endothelial colony-forming cells","volume":"32","author":"Heo","year":"2014","journal-title":"Stem Cells"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1002\/stem.2535","article-title":"Formyl Peptide Receptor 2 Is Involved in Cardiac Repair After Myocardial Infarction Through Mobilization of Circulating Angiogenic Cells","volume":"35","author":"Heo","year":"2017","journal-title":"Stem Cells"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1111\/wrr.12315","article-title":"Stimulation of cutaneous wound healing by an FPR2-specific peptide agonist WKYMVm","volume":"23","author":"Kwon","year":"2015","journal-title":"Wound Repair Regen."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.actbio.2015.07.033","article-title":"Injectable PLGA microspheres encapsulating WKYMVM peptide for neovascularization","volume":"25","author":"Choi","year":"2015","journal-title":"Acta Biomater."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1177\/1947601911423031","article-title":"Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies","volume":"2","author":"Shibuya","year":"2011","journal-title":"Genes Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.3892\/ol.2014.1828","article-title":"Wnt\/beta-catenin signaling pathway may regulate the expression of angiogenic growth factors in hepatocellular carcinoma","volume":"7","author":"Qu","year":"2014","journal-title":"Oncol. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5485738","DOI":"10.1155\/2020\/5485738","article-title":"Exosomes from Placenta-Derived Mesenchymal Stem Cells Are Involved in Liver Regeneration in Hepatic Failure Induced by Bile Duct Ligation","volume":"2020","author":"Jun","year":"2020","journal-title":"Stem Cells Int."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Jun, J.H., Jung, J., Kim, J.Y., Hwang, S.G., Bae, S.H., and Kim, G.J. (2020). Upregulation of C-Reactive Protein by Placenta-Derived Mesenchymal Stem Cells Promotes Angiogenesis in A Rat Model with Cirrhotic Liver. Int. J. Stem Cells.","DOI":"10.15283\/ijsc20052"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1136\/gut.47.2.309","article-title":"Interleukin 6 and liver regeneration","volume":"47","author":"Streetz","year":"2000","journal-title":"Gut"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/j.hep.2003.09.034","article-title":"Transcription factors in liver development, differentiation, and regeneration","volume":"38","author":"Costa","year":"2003","journal-title":"Hepatology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10512","DOI":"10.3748\/wjg.v22.i48.10512","article-title":"Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets","volume":"22","author":"Zhang","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1053\/j.gastro.2008.07.065","article-title":"Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis","volume":"135","author":"Taura","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1097\/00000658-200212000-00002","article-title":"Liver regeneration is an angiogenesis- associated phenomenon","volume":"236","author":"Drixler","year":"2002","journal-title":"Ann. Surg."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1111\/jcmm.14885","article-title":"The protective effect of WKYMVm peptide on inflammatory osteolysis through regulating NF-kappaB and CD9\/gp130\/STAT3 signalling pathway","volume":"24","author":"Hu","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"79","DOI":"10.15283\/ijsc.2015.8.1.79","article-title":"Epigenetic Alterations of IL-6\/STAT3 Signaling by Placental Stem Cells Promote Hepatic Regeneration in a Rat Model with CCl4-induced Liver Injury","volume":"8","author":"Jung","year":"2015","journal-title":"Int. J. Stem Cells"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"816","DOI":"10.5966\/sctm.2015-0191","article-title":"Hypoxic Conditioned Medium From Human Adipose-Derived Stem Cells Promotes Mouse Liver Regeneration Through JAK\/STAT3 Signaling","volume":"5","author":"Lee","year":"2016","journal-title":"Stem Cells Transl. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4302","DOI":"10.4049\/jimmunol.1001310","article-title":"The agonists of formyl peptide receptors prevent development of severe sepsis after microbial infection","volume":"185","author":"Kim","year":"2010","journal-title":"J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1136\/gut.2005.084475","article-title":"An appraisal of the histopathological assessment of liver fibrosis","volume":"55","author":"Standish","year":"2006","journal-title":"Gut"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/2107\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:27:04Z","timestamp":1760160424000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/2107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,20]]},"references-count":37,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijms22042107"],"URL":"https:\/\/doi.org\/10.3390\/ijms22042107","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,20]]}}}